Inhibiting growth of tumors with certain substituted phenoxy dimethyl acids, esters or salts

ABSTRACT

This disclosure describes compositions of matter useful as growth inhibitors of transplanted tumors in mammals; and this invention discloses a method of inducing the regression and/or palliation of various types of tumors in mammals and which are susceptible to treatment by certain substituted phenoxy dimethyl alkanoic acids, esters or salts, said method comprising giving to said mammals an effective amount of a compound of the following formula: ##STR1## [wherein A represents an imidazolyl group or a pyridyl group, 
     l represents 0 or 1, 
     m and n each, which may be the same or different, represents an integer of 1 to 6, and, 
     R represents a hydrogen atom or a lower alkyl group], 
     or a salt thereof; the invention also discloses a method of inhibition (or prevention) of metastasis of the various cancers. 
     The above formula compounds have low toxicity, and it is expected to apply various types of administration thereof such as oral administration and parenteral administration.

This is a continuation of application Ser. No. 874,547, filed Jun. 16, 1986 now U.S. Pat. No. 4,758,580.

BRIEF SUMMARY OF THE INVENTION

This invention relates to a method of inducing the regression and/or palliation of certain types of tumors in mammals and which are susceptible to treatment by certain substituted phenoxy dimethyl alkanoic acids, esters or salts, said method comprising administering to said mammals an effective amount of a compound of the formula ##STR2## [wherein A represents an imidazolyl group or a pyridyl group,

l represents 0 or 1,

m and n each, which may be the same or different, represents an integer of 1 to 6, and,

R represents a hydrogen atom or a lower alkyl group],

or a salt thereof; the invention also relates to a method of inhibition of metastasis of the various tumors, which tumors are susceptible to treatment with certain substituted phenoxy dimethyl alkanoic acids, esters or salts.

BACKGROUND OF THE INVENTION

Among the compounds which fall under the general formula described above, some of ω-(p-substituted phenoxy)-2,2-dimethylalkanoic acid esters are described in Published Unexamined Japanese Patent Application 6667-85 or EP pat. appln. pub. No. 130,077 together with physical data thereof and are known. In the patent application supra, mention is made of utility of these compounds as medicines that they possess excellent activity of inhibiting platelet agglutination.

DETAILED EXPLANATION OF THE INVENTION

This invention relates to a method of inducing the regression and/or palliation of certain types of tumors which are susceptible to treatment by certain substituted phenoxy dimethyl alkanoic acids, esters or salts, said method comprising administering to said mammals an effective amount of a compound of the formula ##STR3## [wherein A represents an imidazolyl group or a pyridyl group,

l represents 0 or 1,

m and n each, which may be the same or different, represents an integer of 1 to 6, and,

R represents a hydrogen atom or a lower alkyl group],

or a salt thereof; the invention also relates to a method of inhibition of metastasis of those cancers susceptible to treatment with certain substituted phenoxy dimethyl alkanoic acids, esters or salts comprising administering to mammals the above compounds.

In the definition of the groups appearing in the formulae in the specification, the term "lower" refers to a straight or branched carbon chain having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms. Accordingly, specific examples of lower alkyl groups include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl (or amyl) group, an isopentyl group, a neopentyl group, a tert-pentyl group, etc.

The compounds represented by general formula (I) described above form salts, which the present invention encompasses.

In particular, preferred examples of the salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.; salts with organic acids such as formic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, benzoic acid, benzenesulfonic acid, etc. and quaternary ammonium salts with alkyl halides such as methyl iodide, etc.

The compounds of the formula (I) and salts thereof can be prepared by the methods described in the specification of Unexamined Japanese Patent Application No. 113988/1983(Sho. 58) laid-open under the laying-open No. 6667/1985(Sho. 60) or Unexamined European Patent Application No. 84304292.0 published under Publication No. 0 130 077. Some of the formula (I) compounds are described in detail in the Examples of the above specifications, and some novel compounds are described in detail in the specification of the present invention.

As a result of investigations on pharmacological activity of ω-(p-substituted phenoxy)-2,2-dimethylalkanoic acids, esters or salts thereof, the present inventors have found that the compounds shown by general formula (I) described above inhibit the growth of tumors susceptible to treatment with certain substituted phenoxy dimethyl alkanoic acids, esters or salts thereof, and extremely low toxicity.

As is evident from results of animal test using mice described later, the anti-tumor activity of the compounds represented by general formula (I) is excellent in showing excellent inhibition effect on various tumors such as Ehrlich solid tumor, MM-46 solid tumor, Meth A solid tumor, Ehrlich ascites tumor, etc. and their toxicity is extremely low. Therefore, the compounds of general formula (I) can be used as safe and potent agents which inhibit the growth of tumors which are susceptible to treatment by such compounds or as agents for inhibiting metastasis of tumors which are also susceptible to such treatment.

Of the compounds included in general formula (I) described above, representative examples are as follows. ##STR4##

Of these compounds, Compounds H, I and J are novel compounds and their process for production will be described later.

(EXAMPLE)

Next, pharmacological activity, toxicity, etc. of the active components are shown below, together with test methods thereof.

Anti-Tumor Test

(1) Anti-tumor test against Ehrlich solid tumor

Ehrlich tumor cells, 2×10⁶, on Day 7 after intraperitoneal transplatation to ddY/SLC mice were subcutaneously transplanted in the left abdomen of ddY/SLC mice (5 week age, male), 10 each grouped into one. The active component was intraperitoneally or orally administered in a definite dose 24 hours after the transplantation, according to the schedule shown in Table 1 (A),(B) or (C). An effect of inhibiting growth of tumor was compared, by measuring the long diameter and short diameter of the tumor on 14, 20 and 21 Days after the transplantation, calculating the tumor size (mm²) and determining a tumor growth inhibition rate of the group administered with the active component to the control group according to the following equation:

    Growth inhibition rate (%) =(C-T)/C×100

T: mean tumor size (mm²) in the active component-administered group

C: mean tumor size (mm²) in the control group

                                      TABLE 1                                      __________________________________________________________________________                              Day 14      Day 21                                                 Route for          Growth      Growth                             Test    Dose Administration                                                                             Size of                                                                               Inhibition                                                                          Size of                                                                               Inhibition                         Compound                                                                               (mg/kg)                                                                             and Days Given                                                                             Tumor (mm.sup.2)                                                                      Rate (%)                                                                            Tumor (mm.sup.2)                                                                      Rate (%)                           __________________________________________________________________________     Compound B                                                                             60   intraperitoneal                                                                            107.3 ± 54.6                                                                       25.7 323.3 ± 163.4                                                                      37.0                                            administration                                                                 (1, 2, 3, 4, 7, 8, 10 & 13                                                     Days)                                                                     100  intraperitoneal                                                                            70.1 ± 33.8                                                                        51.4**                                                                              315.3 ± 235.3                                                                      38.5                                            administration (1, 3, 7,                                                       10, 13 & 14 Days)                                                         200  p.o. (1, 2, 3, 4, 7, 8, 10                                                                 48.7 ± 44.3                                                                        66.3**                                                                              109.2 ± 133.5                                                                      78.7***                                         & 13 Days)                                                        5-Fluorouracil                                                                         25   intraperitoneal                                                                            86.7 ± 35.1                                                                        40.0 217.8 ± 126.2                                                                      57.5**                                          administration                                                                 (1, 2, 3, 4 & 7 Days)                                             Control                  144.4 ± 79.0                                                                            512.8 ± 271.3                          Compound C                                                                             25   intraperitoneal                                                                            191.1 ± 88.8                                                                       18.1 363.1 ± 188.8                                                                      319*                                            administration                                                                 (1, 2, 3, 5, 6, 7 & 9 Days)                                               50   intraperitoneal                                                                            135.0 ± 66.9                                                                       42.4**                                                                              207.9 ± 139.7                                                                      61.0***                                         administration                                                                 (1, 2, 3, 5. 6, 7 & 9 Days)                                               100  intraperitoneal                                                                            107.3 ± 46.7                                                                       54.2***                                                                             190.7 ± 69.1                                                                       64.2***                                         administration                                                                 (1, 2, 3, 5, 6, 7 & 9 Days)                                       Compound I                                                                             25   intraperitoneal                                                                            164.9 ± 96.2                                                                       29.6*                                                                               336.6 ± 160.0                                                                      36.9*                                           administration                                                                 (1, 2, 3, 5, 6, 7 & 9 Days)                                               50   intraperitoneal                                                                            172.8 ± 82.9                                                                       26.2 369.1 ± 203.5                                                                      30.7*                                           administration                                                                 (1, 2, 3, 5, 6, 7 & 9 Days)                                               100  intraperitoneal                                                                            148.7 ± 66.8                                                                       36.5 290.2 ±115.5                                                                       45.6**                                          administration                                                                 (1, 2, 3, 5, 6, 7 & 9 Days)                                       5-Fluorouracil                                                                         25   intraperitoneal                                                                            133.7 ± 61.1                                                                       42.9**                                                                              306.8 ± 166.8                                                                      42.4**                                          administration                                                                 (1, 2, 3, 5, & 6 Days)                                            Mitomycin                                                                              1.0  intraperitoneal                                                                            75.6 ± 31.5                                                                        67.7***                                                                             106.8 ± 62.2                                                                       80.0***                                         administration                                                                 (1, 2, 3, 5, & 6 Days)                                            Control                  234.2 ± 82.1                                                                            323.3 ± 141.5                          Compound J                                                                             50   intraperitoneal                                                                            201.7 ± 48.2                                                                       20.9 344.7 ± 108.4                                                                      19.2                                            administration                                                                 (1, 2, 3, 4, 6, 7, 8,                                                          9 Days)                                                                   100  the same as above                                                                          166.5 ± 65.3                                                                       34.7 263.5 ± 97.1                                                                       38.2                               5-Fluorouracil                                                                         12.5 the same as above                                                                          142.6 ± 36.9                                                                       44.1 280.6 ± 68.9                                                                       34.2                                       25   the same as above                                                                          116.3 ± 44.0                                                                       54.4 252.3 ± 100.3                                                                      40.8                               Control                  255.1 ± 40.9                                                                            426.5 ± 89.3                           __________________________________________________________________________      *p < 0.05,                                                                     **p < 0.01                                                                     ***p < 0.001                                                             

(2) Test against mouse mammalian MM-46 solid tumor

MM-46 Tumor cells, 1×10⁶, on Day 7 after intraperitoneal transplantation to C₃ H/He/SLC mice were subcutaneously transplanted to the left abdomen of C₃ H/He/SLC mice (5 week age, male) of 8 mice each being grouped in one (21 mice for the control group). The active component was orally administered in a definite dose 24 hours after the transplantation according to the schedule shown in Table 2. An effect of tumor growth inhibition was compared by measuring the long diameter and short diameter of the tumor on Days 14 and 21 after the transplantation, calculating the tumor size (mm²) and determining a tumor growth inhibition rate of the active component-administered group to the control group.

                                      TABLE 2                                      __________________________________________________________________________                            Day 14      Day 21                                                    Route for       Growth      Growth                                        Dose Administration                                                                          Size of                                                                               Inhibition                                                                          Size of                                                                               Inhibition                           Test Compound                                                                           (mg/kg)                                                                             and Days Given                                                                          Tumor (mm.sup.2)                                                                      Rate (%)                                                                            Tumor (mm.sup.2)                                                                      Rate (%)                             __________________________________________________________________________     Compund B                                                                               100  p.o. (1-9 Days)                                                                         150.1 ± 52.1                                                                       40.4***                                                                             149.4 ± 84.8                                                                       55.8**                                        200  "        147.9 ± 56.2                                                                       41.3***                                                                             147.5 ± 65.3                                                                       53.4**                                        400  "        131.5 ± 55.2                                                                       47.8***                                                                             157.4 ± 104.0                                                                      53.4**                               Tetrahydrofuryl-                                                                        50   "        216.0 ± 55.1                                                                       14.2 247.0 ± 101.8                                                                      26.9                                 5-fluorouracil                                                                          100  "        214.8 ± 55.6                                                                       14.7 250.1 ± 92.9                                                                       26.0                                 Control                251.9 ± 71.2                                                                            338.0 ± 151.6                            __________________________________________________________________________      *p < 0.05,                                                                     **p < 0.01,                                                                    ***p < 0.001                                                             

(3) Anti-tumor test against methyl cholanthrene-induced Meth A solid tumor:

Meth A tumor cells, 1.5×10⁶, on Day 7 after intraperitoneal transplantation to Balb/C/SLC mice were subcutaneously transplanted to the left abdomen of Balb/C/SLC mice (5 week age, male) of 8 mice each being grouped in one (16 mice for the control group). The active component was orally administered in a definite dose 24 hours after the transplantation according to the schedule shown in Table 3. An effect of tumor growth inhibition was compared by measuring the long diameter and short diameter of the tumor on Days 15 and 21 after the transplantation, calculating the tumor size (mm²) and determining a tumor growth inhibition rate of the active component-administered group to the control group.

                                      TABLE 3                                      __________________________________________________________________________                            Day 15     Day 21                                                     Route for       Growth     Growth                                         Dose Administration                                                                          Size of                                                                               Inhibition                                                                         Size of                                                                               Inhibition                            Test Compound                                                                           (mg/kg)                                                                             and Days Given                                                                          Tumor (mm.sup.2)                                                                      Rate (%)                                                                           Tumor (mm.sup.2)                                                                      Rate (%)                              __________________________________________________________________________     Compound B                                                                              100  p.o. (1-8 Days)                                                                         163.0 ± 41.9                                                                       27.5                                                                               387.9 ± 101.8                                                                      18.8                                           200  "        124.5 ± 6.02                                                                       46.4**                                                                             290.8 ± 100.9                                                                      39.2*                                          400  "        104.4 ± 56.9                                                                       53.6**                                                                             279.3 ± 152.1                                                                      41.6**                                Tetrahydrofuryl-                                                               5-fluorouracil                                                                          50   "        123.4 ± 69.99                                                                      45.1*                                                                              235.8 ± 124.4                                                                      50.7**                                         100  "        93.1 ± 5.03                                                                        58.6**                                                                             264.4 ± 110.6                                                                      44.7**                                Control                224.6 ± 89.8                                                                           477.7 ± 189.8                             __________________________________________________________________________      *p < 0.05,                                                                     **p < 0.01                                                               

(4) Anti-tumor effect against Ehrlich ascites tumor:

Ehrlich tumor cells, 1×10⁶, on Day 7 after intraperitoneal transplantation to ddY/SLC mice were intraperitoneally transplanted to ddY/SLC (5 week age, male) of 10 mice each being grouped in one. The active component was intraperitoneally administered in a definite dose 24 hours after the transplantation according to the schedule shown in Table 4. An effect of tumor growth inhibition was evaluated by a percentage of the median survival day of the administered group versus that of the control group, according to the following equation.

    T/C%=T/C×100

T: median survival day of the administered group

C: median survival day of the control group

                                      TABLE 4                                      __________________________________________________________________________                  Route for  Median    No. of                                               Dose Administration                                                                            Survival  40-day                                       Test Compound                                                                          (mg/kg)                                                                             and Days Given                                                                            Day  T/C (%)                                                                             Survivors                                    __________________________________________________________________________     Compound B                                                                             15   intraperitoneal                                                                           16.0 106  0/8                                                       (1-9 Days)                                                                30   "          22.5 150.0                                                                               1/8                                                  60   "          21.5 143.3                                                                               2/8                                                  100  intraperitoneal                                                                           26.5 176.7                                                                               2/8                                                       administration                                                                 (1, 3, 6, 8 & 10 Days)                                            5-Fluorouracil                                                                         25   intraperitoneal                                                                           24.5 163.3                                                                               0.8                                                       administration                                                                 (1-9 Days)                                                        Control                 15.0 100  0/10                                         __________________________________________________________________________

(5) Anti-tumor test against mice mammary cancer MM-46 ascites tumor:

MM-46 tumor cells, 1×10⁶, on Day 7 after intraperitoneal transplantation to C₃ H/He/CRJ mice (5 week age, male) of 10 mice each being grouped in one. The active component was intraperitoneally administered in a definite dose 24 hours after the transplantation according to the schedule shown in Table 5. An effect of tumor growth inhibition was evaluated by a percentage of the median survival time of the administered group versus that of the control group, according to the following equation.

    T/C%=T/C×100

T: median survival day of the administered group

C: median survival day of the control group

                                      TABLE 5                                      __________________________________________________________________________                  Route of Median                                                           Dose Administration                                                                          Survival  Survivors                                      Test compound                                                                          (mg/kg)                                                                             and Days Given                                                                          Day  T/C (%)                                                                             (90 days)                                      __________________________________________________________________________     Compound B                                                                             6.25 intraperitoneal                                                                         7.0  93.3 0/10                                                        administration                                                                 (1, 2, 3, 4 and 6                                                              Days)                                                                     12.5          7.0  93.3 0/10                                                   25            8.5  113.3                                                                               0/10                                                   50            34.0 453.3                                                                               0/10                                                   100           49.0 653.3                                                                               1/10                                                   200           18.5 246.7                                                                               0/10                                           5-Fluorouracil                                                                         6.25          16.0 213.3                                                                               0/10                                                   12.5          17.0 226.7                                                                               0/10                                                   25            20.0 266.7                                                                               0/10                                           Control               7.5       0/10                                           __________________________________________________________________________

It is known that the value of an animal tumor screen depends on its ability to select new drugs with efficacy against human tumors. It is also known that some rodent tumors (for example, L1210, B-16, etc.) would have predicted the clinical activity of most of the established anticancer drugs.

The active ingredients of the present invention inhibit transplanted mammalian tumor growth (for example, liver cancer, mammary cancer, etc.) in mammals when administered orally or intraperitoneally in amounts ranging from about 12.5 mg to about 400 mg per kilogram of body weight per day.

(6) Inhibition of tumor metastasis:

(a) Inhibition of spontaneous metastasis (to the lymph node) of liver cancer (MH-134) cells in mice

MH-134 tumor cells, 1×10⁶, on Day 7 after intraperitoneal transplantation to C₃ H/He/SLC mice were transplanted to the right leg. On the 11th day after the transplantation, the right leg portion wherein the cancer cells were transplanted were cut off. The test compounds were administered orally in a definite dose 24 hours after the transplantation. In order to confirm metastasis-inhibiting effect, on 20th day of the transplantation the mice were anatomised to observe the metastasis to the lymph node in the inguinal portion. ##EQU1## Further, the weight of the lymph node metastasis tumor in the inguinal portion of anatomised mice was measured. ##EQU2##

                                      TABLE 6(a)                                   __________________________________________________________________________                  Route of  Metastasis-                                                                          Growth inhibition                                         Dose administration                                                                           inhibition                                                                           of the metastasis                                 Test compound                                                                          (mg/kg)                                                                             and days given                                                                           rate (%)                                                                             tumor (%)                                         __________________________________________________________________________     Compound B                                                                             100  oral                                                                           administration                                                                           8.5   33.8                                                           (1, 3, 5, 7, 9, 11, 13                                                         and 15 days)                                                              200  oral      41.2  79.4                                                           administration                                                                 (1, 3, 5, 7, 9, 11, 13                                                         and 15 days)                                                              400  oral      73.9  80.4                                                           administration                                                                 (1, 3, 5, 7, 9, 11, 13                                                         and 15 days)                                                      5-Florouracil                                                                          50   oral      17.7  48.7                                                           administration                                                                 (1, 3, 5, 7, 9, 11, 13                                                         and 15 days)                                                              100  oral      41.2  74.2                                                           administration                                                                 (1, 3, 5, 7, 9, 11, 13                                                         and 15 days)                                                      __________________________________________________________________________

(b) Inhibition of experimental metastasis (to the lung) of melanoma BL-6 in mice:

BL-6 cancer cells, 5×10⁴, were inoculated into the tail veins of male BDF₁ /SLC mice (6 week age) of 6 mice each being grouped in one (13 mice for the control group). The test compounds were administered orally in a definite dose 24 hours after the inoculation. In order to see metastasis-inhibitory effect, on 22th day after the inoculation, the mice were anatomised to observe the metastasis to the lungs. The degree of metastasis was evaluated by the number of pulmonary nodules. ##EQU3## T: Median number of pulmonary nodules of the administered group C: Median number of pulmonary nodules of the control group

                                      TABLE 6(b)                                   __________________________________________________________________________                  Route of    The number of                                                                           Pulmonary                                            Dose administration                                                                             pulmonary nodules                                                                       metastasis-                                  Test compound                                                                          (mg/kg)                                                                             and days given                                                                             range                                                                              median                                                                              inhibition rate (%)                          __________________________________________________________________________     Compound B                                                                             200  Oral administration                                                                        1-20                                                                               10.5 50.0                                                      (1, 2, 3, 5, 6, 7, 8, 9 and                                                    10 days)                                                                  400  Oral administration                                                                        1-14                                                                               6.5  69.0                                                      (1, 2, 3, 5, 6, 7, 8, 9 and                                                    10 days)                                                          Futoraful                                                                              50   Oral administration                                                                        1-49                                                                               13.5 35.7                                                      (1, 2, 3, 5, 6, 7, 8, 9 and                                                    10 days)                                                                  100  Oral administration                                                                        1-16                                                                               6.5  69.0                                                      (1, 2, 3, 5, 6, 7, 8, 9 and                                                    10 days)                                                          Control                  3-87                                                                               21.0 0                                            __________________________________________________________________________

From the above results, it is apparent that the compounds of this invention have effects of inhibition of tumors or inhibition of metastasis of the various tumors susceptible to treatment with the compounds of formula (I). Thus, the compounds of the formula (I) is expected to be useful for treatment of cancer metastasis.

(7) The effectiveness against mouse tumor cells and human tumor cells (in vitro cytotoxicity test)

(a) against mouse tumor cells:

A suspension of cells in a culture medium was transferred into wells in a microplate in an amount of 1×10⁵ cell/well. Test sample diluted with a culture medium was added to the suspension in each well, and the mixture was incubated on the medium at 37° C. for 3 days in atmosphere of air containing 5% carbon dioxide. Thereafter, the incubated cells were recovered from the microplate and the number of live cells was counted by the dye exclusion test using a 0.5% solution of trypan blue and by using a hemocytometer. The cytotoxicity effects against various mice tumor cells were evaluated by the mean dose producing 50%-killing of tumor cells (IC₅₀). The cytotoxicity data for the test compound and that of 5-fluorouracil are given in Table 7(a).

                  TABLE 7 (a)                                                      ______________________________________                                                        IC.sub.50 (μg/ml)                                                           Test compound                                                                  (Compound B)                                                                             5-fluorouracil                                        ______________________________________                                         L-1210           1.9         0.06                                              Ehrlich (carcinoma)                                                                             0.5         0.05                                              MM 46 (mammary cancer)                                                                          0.7         --                                                MH 134 (liver cancer)                                                                           2.2          0.009                                            Meth A (methylcholanthrene-                                                                     0.8         0.1                                               induced cancer)                                                                ______________________________________                                    

(b) against human tumor cells: A suspension of cells in a culture medium was transferred into wells in a microplate in an amount of 5×10⁴ cell/well. Test sample diluted with a culture medium was added to the suspension in each well, and the mixture was incubated at 37° C. for 3 days an atmosphere of air containing 5% carbon dioxide. After skimming, sticking cells were dyed with crystalviolet for 10 minutes. After washing with water, 1% sodium lauryl sulfate solution was added to each well, and the absrobancy (optical density) at 540 m was measured. "% inhibition" was calculated from the following equation. ##EQU4##

The cytotocicity effects against various human tumor cells were evaluated by the mean dose producing 50%-killing of tumor cells (IC₅₀).

                  TABLE 7 (b)                                                      ______________________________________                                                      IC.sub.50 (μg/ml)                                                           Test compound                                                                  (Compound B)                                                                              5-fluorouracil                                         ______________________________________                                         KB (nasal cavity &                                                                            1.15         1.75                                               pharynx cancer)                                                                Hela (uterine cancer)                                                                         2.05                                                            Bowes (melanoma)                                                                              1.00         0.61                                               ACHN (kidney cancer)                                                                          2.30         0.10                                               ______________________________________                                    

Toxicity Test

The active component was orally administered to ddY mice (mean body weight of 35 g, male). No example of death was noted up to the dose of 5,000 mg/kg. Accordingly, the acute toxicity of Compound B is greater than 5,000 mg/kg.

(Effects)

From the foregoing test results, ω-(p-substituted phenoxy)-2,2-dimethylalkanoic acids, esters or salts thereof possess excelent anti-tumor activity but have low toxicity and therefore, effective for use in inhibiting the growth of tumors susceptible to treatment by said acids, esters or salts.

Clinical dose of the tumor inhibiting agent of the present invention is daily 500 to 2,000 mg for adults, preferably 800 to 1,200 mg, in the case of oral administration or in a suppository form. The dose is given once or divided into 2 to 4 smaller doses. The dosage is appropriately varied depending on condition of patient, combination use with other agents, age, etc.

In the case of oral administration, medical preparations are in the form of tablets, capsules, granules or syrups. In the case of perenteral administration, suppositories or injections are applicable. As excipients used for preparation of oral administration, there are lactose, starch, sucrose, talc, magnesium stearate, sorbitol, microcrystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, etc. As bases used for preparation of suppositories, there are polyethylene glycol, lanolin, cocoa butter, Witep Sol (trademark, manufactured by Dynamit Nobel Co., Ltd.).

Hereafter an example of preparing capsules is shown below.

    ______________________________________                                         Preparation of capsules:                                                       ______________________________________                                         Compound B             200    mg                                               Lactose                205    mg                                               Crystalline cellulose  50     mg                                               Hydroxypropyl                                                                  cellulose              15     mg                                               Starch                 25     mg                                               Magnesium stearate     5      mg                                                                      500    mg                                               ______________________________________                                    

According to the composition described above, the main ingredient, lactose and crystalline cellulose are mixed and an aqueous solution of hydroxypropyl cellulose is added thereto. After the mixture is kneaded, grained and dried, magnesium phosphate is added thereto and mixed. The mixture is filled up in No. 1 gelatin capsules to prepare capsules.

Preparation of Compound H:

After 110 mg of sodium hydride (60% suspension in mineral oil) was washed with dry benzene, 10 ml of dry dimethylformamide was added thereto and 264 mg of 3-hydroxypyridine was further added to the mixture with stirring. After vigorous foaming was discontinued, the suspension was heated at 80° C. for 30 minutes with stirring and then cooled to room temperature. A solution of 870 mg of methyl 7-[p-(3-bromopropoxy)phenoxy]-2,2-dimethylheptanoate in 10 ml of dry dimethylformamide was added to the suspension followed by stirring at 60° C. for 5 hours. Thereafter the solvent was removed from the reaction solution under reduced pressure. The remained oily substance was dissolved in benzene, washed with an aqueous saturated hydrogen sodium carbonate solution, water and a saturated saline solution in this order and then dried over anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure. The remaining oily substance was subjected to silica gel column chromatography and the product was eluted out using as an eluent chloroform-methanol solution (50:1). The solvent was distilled off from the eluate under reduced pressure to give the desired methyl 7-[p-[3-(3-pyridyloxy)propoxy]phenoxy]-2,2-dimethylheptanoate as an oily substance. ##STR5##

Preparation of Compound I

Using as a starting material methyl 5-[p-[(3-bromopropoxy)phenoxy]-2,2-dimethylpentanoate in place of methyl 7-[p-(3-bromopropoxy)phenoxy]-2,2-dimethylheptanoate in Preparation of Compound H, similar reaction and treatment were conducted to give the desired methyl 2,2-dimethyl-5-[p-[3-(3-pyridyloxy)propoxy]phenoxy]pentanoate as an oily substance. ##STR6##

Preparation of Compound J

Into 5 ml of dry dimethylformamide containing 150 mg of sodium hydride (60% suspension in mineral oil) was added 292 mg of 2-hydroxypyridine. After stirring the mixture at room temperature for 15 minutes, 1.2 g of ethyl 6-[p-(5-bromopentyloxy)phenoxy]-2,2-dimethylhexanoate was added thereto. The mixture was stirred at room temperature for 12 hours, and thereafter the solvent was removed from the reaction solution under reduced pressure. The remaining oily substance was dissolved in chloroform, washed with water, and then dried over anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure. The remaining oily substance was subjected to silica gel column chromatography and the product was eluted out using as an eluent chloroform-methanol (99:1). The solvent was distilled off from the eluate under reduced pressure to give the desired ethyl 6-[p-[5-(2-pyridyloxy)pentyloxy)phenoxy]-2,2-dimethylhexanoate as an oily substance (495 mg).

NMR spectra (CDCl₃) δ(ppm) 1.16 (6H, s) 6.10 (1H, dd), 1.22 (3H, t) 6,52 (1H, dd), 3.6 - 4,3 (6H, m) 6,76 (4H, s), 4.10 (2H, q).

Mass spectrum M⁺ m/z 443. 

We claim:
 1. A method of inhibiting the growth of tumors in a mammal wherein the growth of said tumors is susceptible to treatment by a compound selected from the group consisting ofethyl 6-[p-{5-(1-imidazolyl)pentyloxy}phenoxy]-2,2-dimethylhexanoate hydrochloride, ethyl 7-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylheptanoate, and ethyl 6-[p-[5-(2-pyridyloxy)pentyloxy]phenoxy]-2,2-dimethylhexanoate, which comprises administering to said mammal an anti-tumor effective amount of said compound.
 2. The method of claim 1 for inhibiting the growth of tumors in a mammal wherein the growth of said tumors is susceptible to treatment by ethyl 6-[p-{5-(1-imidazoyl)pentyloxy}phenoxy]-2,2-dimethylhexanoate hydrochloride, which comprises administering to said mammal an anti-tumor effective amount of said compound.
 3. The method of claim 1 for inhibiting the growth of tumors in a mammal wherein the growth of said tumors is susceptible to treatment by ethyl 7-[p-[5-(1-imidazolyl) pentyloxy]phenoxy]-2,2-dimethylheptanoate, which comprises administering to said mammal an anti-tumor effective amount of said compound.
 4. The method of claim 1 for inhibiting the growth of tumors in a mammal wherein the growth of said tumors is susceptible to treatment by ethyl 6-[p-[5-(2-pyridyloxy)pentytloxy]phenoxy]-2,2-dimethylhexanoate, which comprises administering to said mammal an anti-tumor effective amount of said compound. 